Patients with well-documented chronic hepatitis C are being evaluated to determine the long-term natural history and immune pathogenesis of this disease and to evaluate therapies, particularly in patients who fail to respond to conventional therapy of this common form of chronic liver disease. Recent studies have defined the standard, optimal therapy for chronic hepatitis C as the combination of alpha interferon and ribavirin given for 24 to 48 weeks. This regimen induces a sustained clearance of HCV RNA from serum and improvement in serum aminotransferases and the underlying the liver disease in approximately 40% of patients. For patients who do not become HCV RNA negative with therapy, there are few other options. Current studies of therapy done by the Liver Diseases Section, NIDDK focus upon these patients who fail to respond to the standard therapy of hepatitis C. In one study of long-term ribavirin, patients are initially treated with the combination of alpha interferon and ribavirin: those patients who do not become HCV RNA negative after 24 weeks of combination therapy are then randomized to receive either ribavirin or placebo and to stop interferon treatment. A total of 108 patients have been enrolled in this study and 90 have completed participation (18 months of therapy and follow up). In all, 35 patients have been enrolled in the second phase of the study receiving either ribavirin or placebo and 24 of these have completed the one year course and follow up. Liver histology improved in the ribavirin treated patients, but remained unchanged in the placebo recipients. Fibrosis scores did not change in ribavirin recipients, but worsened in those on placebo. Patients who have a beneficial response to ribavirin (as demonstrated by improvements of aminotransferase levels and improvement in liver histology) will then be treated with long-term ribavirin in an open-label study with follow up liver biopsies every two years. A second study of therapy of non-responders is a multicenter, randomized controlled trial known as Halt-C, which focuses on long-term therapy of chronic hepatitis C with pegylated interferon. Pegylated interferon is an alpha interferon that has been modified by convalent linkage with polyethylene glycol which allows for delayed clearance of the active molecule and a sustained duration of action. Pegylated interferon is given once weekly (instead of three times weekly as for regular interferon) and provides more rigorous and sustained antiviral activity. In this trial, patients are first treated with the combination of pegylated interferon and ribavirin for 24 weeks. Patients who do not become HCV RNA negative are then randomized to receive long-term pegylated interferon therapy or no treatment, being followed at 3 month intervals for up to four years and undergoing liver biopsy every two years. This study is a multicenter U.S. trial sponsored by NIDDK which is being conducted in 10 geographically dispersed medical centers including the Clinical Center of the NIH. A total of 1200 patients will be enrolled in this study, up to 100 at the NIH Clinical Center. To date, 27 patients have been enrolled at the NIH. As a part of this study and other natural history studies of hepatitis C, patients undergo immunological and virological assessment of the serum and liver tissue focusing upon elucidation of the pathogenesis of disease and the determinants of progression and of recovery.